The present invention relates to the measurement of the concentration of constituents or other properties of interest of a material using radiation, preferably near infrared radiation. More particularly, apparatus and methods have been developed for measurement of the concentration of constituents such as hemoglobin and its variants and derivatives, glucose, cholesterol and its combined forms, drugs of abuse, and other analytes of clinical and diagnostic significance in a non-invasive manner. Because the apparatus developed for use of this method does not require the withdrawal of blood in order to perform these measurements, it is particularly suitable for testing in the home on a chronic basis, such as for glucose levels in diabetics and for kidney function, e.g., urea or creatinine testing, in patients undergoing home dialysis.
In addition to home testing, development of clinical testing procedures that do not require blood withdrawal has become an important goal, due to the spread of AIDS and the associated fears among the public and health care personnel. Along with AIDS, other diseases such as hepatitis can be spread through the use of invasive procedures without stringent precautions to assure sterility. A recent article, "Nosocomial transmission of hepatitis B virus associated with the use of a spring-loaded finger-stick device," New England Journal of Medicine, 326(11), 721-725 (1992), disclosed a hepatitis mini-epidemic in a hospital caused by the improper use of an instrument for obtaining blood samples. The article describes how the hospital personnel unintentionally transmitted the virus from patient to patient by misuse of the sampling device. Such transfers, potentially hazardous to healthcare personnel as well as patients, are eliminated by non-invasive testing such as that performed by the subject apparatus and methods.
Non-invasive testing will become particularly effective in the long-term management of diabetes. Improperly controlled glucose levels in diabetes patients can result in damage to the circulatory system, the nervous system, the retina, and other organs. These damages can be largely eliminated by closer control of glucose levels on a daily basis. However, this closer control requires measurement of glucose levels four or more times a day. With current apparatus and methods, a painful finger prick is required for each sample. Furthermore, the part of the apparatus that contacts the blood to produce the required chemical change used in the measurement is disposed of after each sample. The cost to the user of these disposables can reach thousands of dollars per year. The inconvenience and discomfort of the sampling adds to the psychic costs of the process. Finally, the sampling process, conducted by relatively untrained personnel, has been reported to multiply the inherent error in the analytical process by a factor of three to five times. Errors in the sampling process occur as a result of not obtaining a proper blood sample (e.g., the sample may be an admixture of intracellular fluid with the blood sample) and as a result of improper application of the sample to the disposable part of the apparatus.
These deficiencies in currently available apparatus and methods have caused a number of groups to attempt to develop non-invasive apparatus for measurement of concentration of various constituents of blood. Commercially, the most successful apparatus for non-invasive chemical constituent measurements are those for "pulse oximetry", where the apparatus is used to measure relative concentrations of oxyhemoglobin and deoxyhemoglobin. These are both strong absorbers in the near infrared, with crossing broadband features, so ratioing of intensities of radiation at two wavelengths can provide the requisite information. Based in part on the success with hemoglobin, much of the current work on non-invasive measurements for chemical constituents has also used the near-infrared region of the electromagnetic spectrum. Because of the large size of the glucose market, most of the additional research is directed to glucose although it is only a low concentration material with weak absorbance. The region from 700 to 1100 nm in wavelength contains the third overtones of the glucose spectrum, theoretically allows minimization of interferences due to water absorption, and exhibits good penetration of human tissue. Other promising research has used longer wavelengths, from 1100 to about 2500 nm.
Substantially all of this work has been carried out using variants on classic spectrophotometric methods. Such methods typically use detectors which measure the radiation transmitted through or reflected from the sample in relatively narrow wavelength bandpasses. The width of the passband is kept narrow for several theoretical reasons. First, a narrower passband minimizes the practical deviations that can occur relative to the theoretical relationships between constituent concentration and absorbance. Second, measurement with a narrow detector passband allows a better measurement of sharply peaked spectra by providing a measurement closer to the radiation peak. This has been believed to improve specificity, and for full-spectrum measurements, provide a more faithful rendition of the absorbance or reflectance spectrum.
The wavelength passband within which the detector operates can be a property of the source or can be obtained by appropriate filtering means placed between source and sample, between sample and detector, or both. The width of the passband in classic spectrophotometric apparatus is ordinarily chosen to be small with respect to the width of the spectral features of the constituent of interest and the sample, if known. Typically, a passband halfwidth less than 10% of the spectral halfwidth is recommended.
In some apparatus and methods, the source is designed to scan the spectral region of interest, so that the measured wavelength varies over time in a controlled manner. In other cases, the source is transformed into a coded broadband source, whose interaction with the sample is later decomposed into narrow-band responses.
In most of the classic spectrophotometric apparatus and methods, the resultant data initially appear within the apparatus as uncorrected intensity versus wavelength data for the sample. The next important step, performed within the spectrophotometric apparatus, is a logarithmic conversion of the data into absorbance or reflectance units using some reference intensity versus wavelength data for normalization. Extensive data processing of the transformed data is then employed to attempt to isolate the components of the data arising from the constituent(s) of interest and the components arising from the background (due to constituents that are not of interest and instrumental artifacts). A multitude of techniques are employed to perform this isolation, largely based on statistical regression techniques. Examples of this general approach include the work of Rosenthal et al., U.S. Pat. No. 5,028,787 and Clarke, U.S. Pat. No. 5,054,487.
All of these classic methods essentially search for a unique response or pattern of responses due to the constituent of interest at one or more specific wavelengths (or narrow wavelength passbands) and then attempt to separate these effects from the effects due to background constituents at the same narrow wavelength passbands. However, glucose and many other constituents of interest possess only weak broadband spectral features in the wavelength ranges of interest. Furthermore, the measurement environment is generally a mixture containing many constituents with overlapping but different broadband spectral structures, several of which, including water and hemoglobin, are strong absorbers in the region. In non-invasive clinical measurements, the problems are compounded by the presence of multiple diffuse radiation scattering centers in the tissue. These situations are contrary to the basic assumptions of spectrophotometry, and its apparatus and methods are ill-suited to dealing with the resultant data.
Spectra with weak, low resolution features and overlapping backgrounds are, however, commonly found in examination of colored objects by reflected, emitted, or transmitted light in the visible wavelength range. The human eye can distinguish wavelength shifts as small as 2 nm, and can distinguish small wavelength shifts even under variable illumination conditions. Therefore, the present invention is based on concepts analogous to those employed in the human visual system and in colorimetric apparatus.
In apparatus for measuring color (as opposed to concentration), two methods are commonly employed. Traditional (tristimulus) colorimetry employs three detectors with spectral responses approximating those of the visual cones in the human eye (shown in FIG. 1a, the CIE Standard Observer) to create an apparatus with spectral sensitivity approximating that of the eye. To improve the approximation, newer devices employ sets of narrow-band detectors to measure the entire visual spectrum at substantially constant sensitivity and then apply software algorithms to simulate the color response of the eye. In both cases, resultant outputs may be transformed by convolving the Standard Observer response with the known spectra of the source to generate data representative of the color of the object being measured.
Data obtained by these colorimetric devices are often presented in transformed co-ordinate spaces for easier interpretation. Examples of such spaces are shown in FIGS. 1b and c. FIG. 1b is the CIE chromaticity coordinate system, while FIG. 1c is the CIE Lab coordinate system. Results presented in these systems are interpretable as hues, chromas, saturations, brightnesses, and other related terms that are more easily related to human perceptions without further mathematical transformation. The CIE Lab system attempts to create a coordinate space that is linear with perceived color differences. These systems have been used in the reflectance or transmittance mode to measure the color of a reflective or transmissive sample. None of these systems has been used to directly measure the concentration of a constituent or constituents of a sample.
U.S. Pat. No. 5,321,265, the disclosure of which is incorporated herein by reference, discloses a basic concept for creating a system analogous to human color perception and to colorimetry using infrared sources and appropriate detection means for measuring the concentration of constituents of a sample. Briefly, the disclosed methods and apparatus use a broadband radiation source to illuminate a sample held in a chamber. Radiation from the source is passed through a plurality of spectrally overlapping filters before reaching detection means which detect radiation transmitted, reflected or emitted from the sample and thereby measure the sample's "color" in the region of the spectrum defined by the filter and detector responses. U.S. patent applications Ser. No. 130,257 now U.S. Pat. No. 5,434,412 and Ser. No. 182,572 now U.S. Pat. No. 5,424,545 concern modifications to the basic apparatus and methods to achieve better results. The present invention concerns further methods and apparatus which may be employed toward the same objective. These methods and apparatus are all directed to improving the accuracy, sensitivity and repeatability of non-invasive measurements of materials such as glucose. The present invention, however, is not limited to overlapping detectors, although it is preferable that at least some of the detectors overlap. Similarly, while broadband detectors are preferred, it is possible to use some, or all, narrow band sources or detectors.
Accordingly, an object of the invention is to provide an apparatus for obtaining a non-invasive measure of the concentration of a constituent of interest using the infrared portion of the spectrum.
A further object of the invention is to provide methods for obtaining a measure of the concentrations in blood or in tissue of clinically important analytes in a non-invasive manner.
These and other objects and features of the invention are achieved by the methods and apparatus described in the Summary of the Invention, the Detailed Description and the Drawing.